Obesity can be viewed as an energy balance disorder, arising when energy input exceeds energy output, with most of the excess calories converted into triglycerides and stored in the adipose tissue. Medications currently approved for the treatment of obesity attempt to restore energy balance primarily by decreasing energy input by either suppressing appetite or interfering with lipid absorption in the small intestine. Because of the rapid increase in the prevalence of obesity worldwide and the lack of efficacy of current medical therapies, novel pharmacologic therapies for obesity are required.
One potential therapeutic strategy involves inhibiting triglyceride synthesis. Although triglycerides are essential for normal physiology, excess triglyceride accumulation results in obesity and, particularly when it occurs in nonadipose tissues, is associated with insulin resistance. DGAT is an enzyme that catalyzes the last step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of a 1,2-diacylglycerol with a fatty acyl-CoA resulting in Coenzyme A and triacylglycerol. Two enzymes that display DGAT activity have been identified: DGAT1 (acyl coA-diacylglycerol acyl transferase 1, see Cases et al, Proc. Natl. Acad. Sci. 95:13018-13023, 1998) and DGAT2 (acyl coA-diacylglycerol acyl transferase 2, see Cases et al, J. Biol. Chem. 276:38870-38876, 2001). DGAT1 and DGAT2 do not share significant protein sequence homology. Importantly, DGAT1 knockout mice are protected from high fat diet-induced weight gain and insulin resistance (Smith et al, Nature Genetics 25:87-90, 2000). The phenotype of the DGAT1 knockout mice suggest that a DGAT1 inhibitor has utility for the treatment of obesity and obesity-associated complications.    WO2006113919 discloses aryl alkyl acid derivatives having DGAT inhibitory activity.    WO2006044775 discloses biphenyl-4-yl-carbonylamino acid derivatives having DGAT inhibitory activity.    WO2006134317 discloses oxadiazole derivatives having DGAT inhibitor activity.    WO2006082952 discloses amide derivatives having DGAT inhibitor activity.    WO2006082010 discloses compounds having DGAT inhibitor activity.    WO 2006/019020 A1 and WO 2006/004200 A1 disclose urea derivatives having DGAT inhibitory activity.    WO 2005/044250 A1 disclose sulfonamide compounds having DGAT inhibitory activity.    WO 2005/013907 A2 discloses pyrrolo[1,2-b] derivatives having DGAT inhibitory activity.    WO 2005/072740 A2 discloses compounds having DGAT inhibitory activity.    JP 2005/206492 A2 disloses sulfonamide compounds having DGAT inhibitory activity.    JP 2004/067635 A2 discloses phosphonic acid diesters having DGAT inhibitory activity.    US 2004/0224997 A1 discloses aryl alkyl acid derivatives having DGAT1 inhibitory activity.    WO 2004/04775 A2 discloses fused bicyclic nitrogen-containing heterocycles having DGAT inhibitory activity.    US 2005/0101660 A1 discloses dibenzo-p-dioxane derivatives having DGAT inhibitory activity.    EP 0573696 A1 discloses heterobiaryl derivatives of the general structure R1NH—X1—X2—X3—Y1—Y1—Y3—Y4-E having aggregation inhibiting activity.    US 2005/0143422 A1 relates to biaryl sulfonamides and their use as metalloproteinase inhibitors.    WO 00/25780 relates to amine compounds of the general structure X—N(R)—B-D and their use as IMPDH inhibitors.    WO 01/42241 relates to substituted pyridazine compounds having cytokine inhibitory activity.    WO 02/055484 A1 relates to a compound of the general formula R1—X1—Y—X2-A-B—X3—N(—X4—R2)—Z—Ar, wherein A and B represent 5- or 6-membered aromatic rings. The compound can be used as a blood lipid depressant.    WO 02/085891 A1 relates to 2,6-substituted chroman derivatives which are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.    WO 02/11724 A2 relates to pharmaceutical compositions comprising 2-pyridinamines which can be used for preventing ischemic cell death.    WO 03/062215 A1 relates to substituted thia-/oxa-/pyrazoles for inhibiting the activity of one or more protein kinases.    WO 2004/000788 A1 relates to ureido-substituted aniline compounds which are useful as serine protease inhibitors.    WO 2004/032882 A2 relates to oxazole derivatives which are useful in the treatment of diseases associated with inappropriate protein kinase activity.    WO 2004/041810 A1 relates to nitrogen-containing heteroaryl compounds which are useful for treatment of protein kinase mediated disorders.    WO 2004/046133 A1 relates to amino-heterocycles useful as VR-1 antagonists for treating pain.    WO 2004/089286 A2 relates to nitrogen-containing heteroaryl compounds which are useful for treating disorders associated with abnormal tyrosine kinase activity.    WO 2004/110350 A2 relates to compounds of the general structure (A)-LA-(B)-LB-(C)-LC-(D) wherein A, B, C and D represent aryl/heteroaryl moieties. The compounds are useful for treating neurodegenerative diseases.    WO 2005/012295 A1 relates to substituted thiazole benzoisothiazoledioxo derivatives which are useful for treating diabetes.    WO 2005/016862 A1 relates to substituted arylalkanoic acid derivatives having prostaglandin production-suppressing activity.    WO 2005/085227 A1 relates to pyridine compounds which are useful as inhibitors of PKB/AKT kinase activity and in the treatment of cancer and arthritis.    WO 2005/100344 A1 relates to compounds which comprise substituted pyridazine and pyrimidine moieties. These compounds are useful for inhibiting the activity of a serine/threonine protein kinase.    WO 2005/116003 A2 relates to substituted oxazolobenzoisothiazole dioxide derivatives which are useful in the treatment of diabetes.    WO 98/46574 relates to pyridazine and phthalazine derivatives which are useful as. anticonvulsants.    WO 99/24404 relates to substituted pyridine compounds which are useful as anti-inflammatory agents.